Abstract
Biologic drugs are large molecule pharmaceuticals that do not cross the blood–brain barrier (BBB), which is formed by the brain capillary endothelium. Biologics can be re-engineered for BBB transport as IgG fusion proteins, where the IgG domain is a monoclonal antibody (MAb) that targets an endogenous BBB transporter, such as the insulin receptor (IR) or transferrin receptor (TfR). The IR and TfR at the BBB transport the receptor-specific MAb in parallel with the transport of the endogenous ligand, insulin or transferrin. The kinetics of BBB transport of insulin or transferrin, or an IRMAb or TfRMAb, can be quantified with separate mathematical models. Mathematical models to estimate the half-time of receptor endocytosis, MAb or ligand exocytosis into brain extracellular space, or receptor recycling back to the endothelial luminal membrane were fit to the brain uptake of a TfRMAb or a IRMAb fusion protein in the Rhesus monkey. Model fits to the data also allow for estimates of the rates of association of the MAb in plasma with the IR or TfR that is embedded within the endothelial luminal membrane in vivo. The parameters generated from the model fits can be used to estimate the brain concentration profile of the MAb over time, and this brain exposure is shown to be a function of the rate of clearance of the antibody fusion protein from the plasma compartment.
Highlights
The IgG domain of the fusion protein is a monoclonal antibody (MAb) that targets an exofacial epitope on certain endogenous peptide receptor-mediated transcytosis (RMT) systems expressed on the blood–brain barrier (BBB) membrane
In an effort to better understand the mechanisms of BBB transport of a TfRMAb, a MAb against HIR (HIRMAb), or the fusion proteins generated from these antibodies, a mathematical model has been recently developed [35]
Tosis (k3) at the BBB, HIRMAb exocytosis into the brain extracellularspace space (ECS) (k7), or insulin receptor (IR) receptor recycling receptor recycling within the intra-endothelial compartment (k6 ), and these parameters within the intra-endothelial compartment (k6), and these parameters were estimated by fitting the IRMAb model (Figure 6) to the experimentally observed brain uptake of the HIRMAb-IDUA fusion protein in the Rhesus monkey [36]
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. The comparison of brain uptake of TfRMAbs with different affinity for the TfR is typically evaluated at a high injection dose (ID), e.g., 30–50 mg/kg, which produces plasma concentrations of the TfRMAb that selectively saturate the binding sites on the BBB TfR with the high-affinity TfRMAb. In an effort to better understand the mechanisms of BBB transport of a TfRMAb, a HIRMAb, or the fusion proteins generated from these antibodies, a mathematical model has been recently developed [35]. The results of this mathematical model are analyzed with respect to the role of the endogenous ligand, Tf or insulin, the role of high and low affinity of the TfRMAb for the BBB receptor, and the extent to which the pharmacokinetics of plasma clearance determines the brain exposure of the fusion protein
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